Bcl-2 family genes have a key role in controlling programmed cell death in neurons. We have found evidence that bcl-2 family genes are dysregulated and PCD occurs in both animal models and TBI in humans. The hypothesis of this proposal is that altered expression of bcl-2 family gene occurs after brain trauma and contributes to programmed cell death, oxidative stress, neuronal death, and adverse behavioral outcome. Specific aims are as follows: 1. Characterize alterations in expression of the bcl-2 family genes (including bcl-2, bcl-x, Bax) that occur after CCI in mice. 2. Test whether bcl-2 expression inhibits PCD, oxidative stress and improves histological and behavioral outcome after CCI by use of a transgenic mouse that over-expresses bcl-2. 3. Test whether Bax expression is necessary to trigger PCD after CCI, and whether Bax expression mediates oxidative stress, adverse histological and behavioral outcome by use of Bax-disrupted transgenic mice subjected to CCI. 4. Test whether over-expression of bcl-x-1 by replication deficient herpes simplex viral vectors can protect hippocampal neurons against CCI. 5. Determine if similar alterations in bcl-2 family expression occur in human TBI by examining expression of bcl-2 and Bax in human tissue removed during decompressive craniotomies and CSF from ventriculostomies. Furthermore, determine if there is evidence of apoptosis in CSF (nucleosomes). Correlate these findings with long term outcome as determined by the Glasgow outcome score (GOS) and other measures. The proposed experiments address the key issues regarding the alteration of bcl-2 family genes in traumatic brain injury: Do bcl-2 family genes regulate cell death after trauma or is their altered expression an epiphenomena in cells already destined to live or die, and are these changes relevant to human head trauma? If these experiments support the hypothesis that bcl-2 family genes regulate cell death after trauma, alteration of expression of these genes or mimicking or inhibiting their effects could provide new strategies for treatment of traumatic brain injury.